Structure and interactions of the human programmed cell death 1 receptor.

Journal article

PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C" strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1 · ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.

Authors: Cheng, X; Veverka, V; Radhakrishnan, A; Waters, L; Muskett, F

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 288
• Issue: 17
• Pages: 11771-11785
• Publication date: 2013-04-01
• DOI: 10.1074/jbc.m112.448126
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Surface Plasmon Resonance; Programmed Cell Death 1 Receptor; T-Lymphocytes; Structure-Activity Relationship; Antigens, CD274; Animals; Mice; Protein Structure, Secondary; Nuclear Magnetic Resonance, Biomolecular; Humans; Programmed Cell Death 1 Ligand 2 Protein; Protein Binding; Antigens, CD80; Models, Immunological; Antigen-Presenting Cells; Cell Communication